Associations of Nephron Number, Birth Weight, and Causes of Death in a Community at High Risk of Hypertension and Cardiovascular Disease

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Rationale and Objective Low Birth Weight (LBW) and low nephron number may increase the risk of hypertension and cardiovascular disease (CVD). Study Design Total glomerular number was determined by stereological analysis of autopsy kidneys from 336 subjects. Health Department-recorded birth weights were obtained for 204 subjects who were ≤ 55 years old. Outcomes Birth weight, nephron number. Predictors Hypertension, CVD, age, sex, body mass index, poverty index, and APOL1 genotype. Analytical Approach Relationships were investigated by group comparisons and regression models. Settings and Participants Performance sites: Autopsies, University Medical Center, Jackson, MS; Stereology, Department of Anatomy and Developmental Biology, Monash University, Melbourne; APOL1 genotyping, Basic Research Laboratory, Center for Cancer Research, National Institutes of Health, Frederick, Maryland. Results 170 subjects having birth weights were adults, 29% of adults were hypertensive, and 40% died of CVD. Genotyping identified 22 Black subjects with two APOL1 risk alleles. A median of 718,409 glomeruli per kidney was found for subjects with LBW (< 2.5 kg), which was significantly less than the median of 936,937 glomeruli found with birth weights from 3.0 to 4.0 kg (p <0.001). Among adults ≤ 55 years old, hypertension correlated with age (p < 0.001) and the severity of glomerulosclerosis (p < 0.001), and CVD death correlated with hypertension (p = 0.01). However, neither LBW nor nephron number was associated with hypertension or CVD death, nor with an APLO1 high-risk genotype. Among subjects aged 65-89 years, increased glomerulosclerosis was associated with a lower median glomerular number (759,623; p=0.02) and with hypertension (p<0.01). Limitations Relationships of predictors to outcomes are abridged by death at recruitment. Conclusions LBW and low nephron number were not related to hypertension or CVD in adults ≤ 55 years of age, but a glomerulosclerosis-related reduction in glomerular number may contribute to hypertension and CVD in later life. Plain-Language-Summary The nephron is the basic functional unit of the kidney, and nephron number is directly related to birth weight. It is proposed that hypertension and cardiovascular disease (CVD) risk are the result of reduced nephron numbers in persons born with low birth weight (LBW). In this study, we show that the median number of nephrons in persons born at LBW is 719,409 (compared to nearly 1 million with normal birth weight). We suggest that a nephron number ≤720,000 indicates a nephron deficit. In individuals up to 55 years old, this deficit is not associated with hypertension. But after 55, the number of nephrons is further reduced by aging and may contribute to hypertension and CVD death in late middle age.

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